Musashi-1 Regulates MIF1-Mediated M2 Macrophage Polarization in Promoting Glioblastoma Progression

Yi-Ping Yang,Mong-Lien Wang,Yueh Chien,Chian-Shiu Chien,Man-Sheung Chan,Yi-Wei Chen,Andy Chi-Lung Lee,Wen-Chang Lin,Hsin-I Ma,Ming-Teh Chen,Wen-Liang Lo,Aliaksandr A Yarmishyn,Pin-I Huang

doi:10.3390/cancers13081799

Abstract

Simple SummaryGlioblastoma (GBM) is the most lethal type of brain cancer. It is well known that the malignancy of cancers is dependent not only on the oncogenic properties of the tumor cells, but also on the composition of the tumor microenvironment, which includes macrophages of the immune system. The prevalence of M2 type macrophages usually promotes tumor progression as opposed to tumor-suppressing function of M1 type macrophages. In our previous studies, we identified Musashi-1 (MSI1) RNA-binding protein as a principal oncogenic factor in GBM. In this study, in a pursuit of finding secreted factors that may alter tumor microenvironment in GBM, we identified MIF1 cytokine to be positively regulated by MSI1. Moreover, we found that MSI1-mediated MIF1 secretion promotes differentiation of macrophages into pro-oncogenic M2 phenotype. The oncogenic role of MSI1/MIF1/M2 macrophage regulatory axis was also confirmed in GBM mouse models, which makes it a promising target for novel drug discovery.Glioblastoma (GBM) is the most malignant brain tumor which is characterized by high proliferation and migration capacity. The poor survival rate has been attributed to limitations of the current standard therapies. The search for novel biological targets that can effectively hamper tumor progression remains extremely challenging. Previous studies indicated that tumor-associated macrophages (TAMs) are the abundant elements in the tumor microenvironment that are closely implicated in glioma progression and tumor pathogenesis. M2 type TAMs are immunosuppressive and promote GBM proliferation. RNA-binding protein Musashi-1 (MSI1) has recently been identified as a marker of neural stem/progenitor cells, and its high expression has been shown to correlate with the growth of GBM. Nevertheless, the relationship between MSI1 and TAMs in GBM is still unknown. Thus, in our present study, we aimed to investigate the molecular interplay between MSI1 and TAMs in contributing to GBM tumorigenesis. Our data revealed that the secretion of macrophage inhibitory factor 1 (MIF1) is significantly upregulated by MSI1 overexpression in vitro. Importantly, M2 surface markers of THP-1-derived macrophages were induced by recombinant MIF1 and reduced by using MIF1 inhibitor (S,R)-3-(4-hHydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid (ISO-1). Furthermore, GBM tumor model data suggested that the tumor growth, MIF1 expression and M2 macrophage population were significantly downregulated when MSI1 expression was silenced in vivo. Collectively, our findings identified a novel role of MSI1 in the secretion of MIF1 and the consequent polarization of macrophages into the M2 phenotype in promoting GBM tumor progression.

Highlights

Glioblastoma multiforme (GBM) is the most common and aggressive human brain cancer which is categorized as a grade IV tumor according to the World Health Organization [1]
We identified macrophage inhibitory factor 1 (MIF1) as a cytokine regulated by MSI1 and mediating M2 polarization of macrophages, and such regulation was found to be associated with a malignant phenotype
The conditioned medium was exposed to cytokine array analysis, and it was revealed that MSI1 overexpression resulted in upregulation of the cytokine macrophage inhibitory factor 1 (MIF1) (Figure 1A)

Summary

Introduction

Glioblastoma multiforme (GBM) is the most common and aggressive human brain cancer which is categorized as a grade IV tumor according to the World Health Organization [1]. GBM is classified as primary or secondary depending on the cause of formation. Primary GBM is malignant from the beginning and is highly prone to metastasis, whereas secondary GBM, which occurs in ~5% of glioblastoma patients, develops from lower-grade tumors [2]. Musashi-1 (MSI1) is a neural stem cell marker expressed at increased levels in a developing nervous system. This marker is expressed abundantly in high-grade gliomas and correlates with poor prognosis. The most well-characterized mode of action of MSI1 is by inhibition of translation, in particular, its interaction with poly(A)-binding protein (PABP) was reported to disrupt the formation of an active translation complex [10]

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